N-(mercaptoalkyl)amides

ABSTRACT

Novel N-(mercaptoalkyl)amides of the formula ##STR1## wherein R 1  is lower alkyl, cyclolower alkyl, aryl or heteroaryl; 
     R 2  is (COR 3 )-aryl, heteroaryl, substituted (COR 3 )-aryl or substituted heteroaryl, wherein the substituents are 1-3 substituents selected from the group consisting of carboxy, alkoxycarbonyl, lower alkyl, hydroxy, halo, lower alkoxy, cyclolower alkyl, cyano, trifluoromethyl, phenyl, phenoxy and phenylthio; 
     R 3  is --OR 4  or --NR 4  R 5  ; 
     R 4  and R 5  are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl and aryl lower alkyl, or R 4  and R 5  together with the nitrogen to which they are attached form a 5-, 6- or 7-membered ring; 
     Q is hydrogen or R 6  CO--; 
     R 6  is hydrogen, lower alkyl or aryl; and 
     m is 1 or 2; 
     and the pharmaceutically acceptable salts thereof useful in the treatment of cardiovascular disorders, nephrotoxicity and pain conditions and combinations of N-(mercaptoalkyl)amides and atrial natriuretic factors or angiotensin converting enzyme inhibitors useful for treating cardiovascular disorders are disclosed.

BACKGROUND OF THE INVENTION

The present invention relates to N-(mercaptoalkyl)amides useful in thetreatment of cardiovascular disorders and pain conditions.

Cardiovascular disorders which may be treated with compounds of thepresent invention include hypertension, congestive heart failure, edemaand renal insufficiency.

Human hypertension represents a disease of multiple etiologies. Includedamong these is a sodium and volume dependent low renin form ofhypertension. Drugs that act to control one aspect of hypertension willnot necessarily be effective in controlling another.

Enkephalin is a natural opiate receptor agonist which is known toproduce a profound analgesia when injected into the brain ventricle ofrats. It is also known in the art that enkephalin is acted upon by agroup of enzymes known generically as enkephalinases, which are alsonaturally occurring, and is inactivated thereby.

U.S. Pat. No. 4,513,009 to Roques et al discloses compounds having theformula ##STR2## wherein R¹ includes alkyl and optionally substitutedphenyl, n is 0 or 1 and R² includes phenyl and substituted alkyl. Thecompounds are disclosed by Roques et al as principally havingenkephalinase inhibitory activity, but are also said to beantihypertensives.

European Patent Application 161,769 discloses enkephalinase inhibitorsof the formula ##STR3## wherein R₂ includes alkyl, aryl and arylalkyl,R₃ includes hydrogen, alkyl, aryl, heteroaryl, arylalkyl andheteroarylalkyl, and n is 1-15.

It is known that the heart secretes a series of peptide hormones calledatrial natriuretic factors (ANF) which help to regulate blood pressure,blood volume and the excretion of water, sodium and potassium. ANF werefound to produce a short-term reduction in blood pressure and to beuseful in the treatment of congestive heart failure. See P. Needleman etal, "Atriopeptin: A Cardiac Hormone Intimately Involved in Fluid,Electrolyte and Blood-Pressure Homeostasis", N. Engl. J. Med., 314, 13(1986) pp. 828-834, and M. Cantin et al in "The Heart as an EndocrineGland", Scientific American, 254 (1986) pg. 7681. U.S. Pat. No.4,740,499 to Olins discloses a method of prolonging the effect of atrialpeptides comprising co-administering thiorphan (a compound within thescope of U.S. Pat. No. 4,513,009) or kelatorphan with an atrial peptide.

A class of drugs known to be effective in treating some types ofhypertension is ACE inhibitors, which compounds are useful in blockingthe rise in blood pressure caused by increases in vascular resistanceand fluid volume due to the formation of angiotensin II from angiotensinI. For a review of ACE inhibitors, see M. Wyvratt and A. Patchett,"Recent Developments in the Design of Angiotensin Converting EnzymeInhibitors" in Med. Res. Rev. Vol. 5, No. 4 (1985) pp. 483-531.

SUMMARY OF THE INVENTION

Novel compounds of the present invention are represented by the formula##STR4## wherein R₁ is lower alkyl, cyclolower alkyl, aryl orheteroaryl;

R₂ is (COR₃)-aryl, heteroaryl, substituted (COR₃)-aryl or substitutedheteroaryl, wherein the substituents are 1-3 substituents selected fromthe group consisting of carboxy, alkoxycarbonyl, lower alkyl, hydroxy,nitro halo, lower alkoxy, cyclolower alkyl, cyano, trifluoromethyl,phenyl, phenoxy and phenylthio;

R₃ is --OR₄ or --NR₄ R₅ ;

R₄ and R₅ are independently selected from the group consisting ofhydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl andaryl lower alkyl, or R₄ and R₅ together with the nitrogen to which theyare attached form a 5-, 6- or 7-membered ring;

Q is hydrogen or R₆ CO--;

R₆ is hydrogen, lower alkyl or aryl; and

m is 1 or 2;

and the pharmaceutically acceptable salts thereof.

A preferred group of compounds of formula I is that wherein R₂ is(COR₃)-phenyl, nitro or carboxy-substituted (COR₃)-phenyl or pyridyl.Yet another preferred group of compounds of formula I is that wherein R₃is hydroxy, lower alkoxy or aryl lower alkoxy.

Preferred values for Q are hydrogen and acyl. Other preferred compoundsare those wherein R₁ is phenyl or lower alkyl-substituted phenyl, forexample tolyl. A preferred value for m is 1.

Especially preferred compounds of formula I are those wherein R₁ isphenyl or tolyl, m is 1, R₂ is (COR₃)-phenyl, nitro orcarboxy-substituted (COR₃)-phenyl, or pyridyl and R₃ is hydroxy oralkoxy.

The invention also relates to the treatment of cardiovascular diseaseswith a combination of an N-(mercaptoalkyl)amide of the present inventionand an atrial natriuretic factor (ANF) and with a combination of anN-(mercaptoalkyl)amide of the present invention and an angiotensinconverting enzyme (ACE) inhibitor.

Other aspects of the invention relate to pharmaceutical compositionscomprising an N-(mercaptoalkyl)amide of this invention, alone or incombination with an ANF or an ACE inhibitor, and to methods of treatmentof cardiovascular diseases comprising administering anN-(mercaptoalkyl)amide of this invention, alone or in combination withan ANF or an ACE inhibitor, to a mammal in need of such treatment.

Still another aspect of the invention relates to a method of treatingpain conditions by administering an N-(mercaptoalkyl)amide of thisinvention, thereby inhibiting the action of enkephalinase in a mammaland eliciting an analgesic effect. Analgesic pharmaceutical compositionscomprising said N-(mercaptoalkyl)amides are also contemplated.

An additional aspect of the invention relates to a method of treatingnephrotoxicity resulting from immunosuppression therapy byadministration of an N-(mercaptoalkyl)amide of this invention.

DETAILED DESCRIPTION

As used herein, the term "lower alkyl" means straight or branched alkylchains of 1 to 6 carbon atoms, and "lower alkoxy" similarly refers toalkoxy groups having 1 to 6 carbon atoms. Cyclolower alkyl means cyclicalkyl groups of 3 to 6 carbon atoms.

"Aryl" means mono-cyclic or fused ring bicyclic carbocyclic aromaticgroups having 6 to 10 ring members and "heteroaryl" means mono-cyclic orfused ring bicyclic aromatic groups having 5-10 ring members wherein 1-2ring members are independently nitrogen, oxygen or sulfur, wherein thecarbon ring members of the aryl and heteroaryl groups are substituted byzero to three substituents selected from the group consisting ofcarboxy, alkoxycarbonyl, nitro, lower alkyl, hydroxy, halo, loweralkoxy, cyclolower alkyl, cyano, trifluoromethyl, phenyl, phenoxy orphenylthio. Examples of carbocyclic aryl groups are phenyl, α-naphthyland β-naphthyl, and examples of heterocyclic aryl groups are furyl,thienyl, pyrrolyl, benzofuryl, benzothienyl, indolyl and pyridyl. Allpositional isomers, e.g. 2-pyridyl, 3-pyridyl, are contemplated.

"Halo" refers to fluorine, chlorine, bromine or iodine radicals.

Certain compounds of the invention are acidic e.g., those compoundswhich possess a carboxyl group. These compounds form pharmaceuticallyacceptable salts with inorganic and organic bases. Examples of suchsalts are the sodium, potassium, calcium, aluminum, gold and silversalts. Also included are salts formed with pharmaceutically acceptableamines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

The salts may be formed by conventional means, as by reacting the freeacid form of the product with one or more equivalents of the appropriatebase in a solvent or medium in which the salt is insoluble, or in asolvent such as water which is then removed in vacuo or by freeze-dryingor by exchanging the cations of an existing salt for another cation on asuitable ion exchange resin.

Compounds of formula I have at least one asymmetrical carbon atom andtherefore include various stereoisomers. The invention includes all suchisomers both in pure form and in admixture, including racemic mixtures.

An aspect of the present invention described above relates to thecombination of a compound of formula I with an ANF. As indicated byNeedleman et al., a number of ANF have been isolated so far, all havingthe same core sequence of 17 amino acids within a cysteine disulfidebridge, but having different N-termini lengths. These peptides representN-terminal truncated fragments (21-48 amino acids) of a commonpreprohormone (151 and 152 amino acids for man and rats, respectively).Human, porcine and bovine carboxy-terminal 28-amino acid peptides areidentical and differ from similar peptides in rats and mice in that theformer contain a methionine group at position 12 while the lattercontain isoleucine. Various synthetic analogs of naturally occurringANF's also have been found to have comparable biological activity.Examples of ANFs contemplated for use in this invention are α human AP21 (atriopeptin I), α human AP 28, α human AP 23 (atriopeptin II orAPII), α human AP 24, α human AP 25, α human AP 26, α human AP 33, andthe corresponding rat sequence of each of the above wherein Met 12 isIle. See Table I for a comparison of the peptides.

                  TABLE I                                                         ______________________________________                                        HUMAN                                                                         PEPTIDE                                                                        AP 33                                                                                ##STR5##                                                              AP 28  SLRRSSCFGGRMDRIGAQSGLGCNSFRY                                           AP 26  RRSSCFGGRMDRIGAQSGLGCNSFRY                                             AP 25  RSSCFGGRMDRIGAQSGLGCNSFRY                                              AP 24  SSCFGGRMDRIGAQSGLGCNSFRY                                               AP 23  SSCFGGRMDRIGAQSGLGCNSFR.sup.                                           AP 21  SSCFGGRMDRIGAQSGLGCNS                                                  where the amino acids are designated by their single-letter                   abbreviations, namely                                                         A      Ala     Alanine     M    Met   Methionine                              C      Cys     Cysteine    N    Asn   Asparagine                              D      Asp     Aspartic acid                                                                             P    Pro   Proline                                 F      Phe     Phenylalanine                                                                             Q    Gln   Glutamine                               G      Gly     Glycine     R    Arg   Arginine                                I      Ile     Isoleucine  S    Ser   Serine                                  L      Leu     Leucine     Y    Tyr   Tyrosine;                               M* is replaced by I (Ile), in the rat peptide; and the two C.sup.  (Cys)      residues are connected by a disulfide bridge.                                 ______________________________________                                    

Another aspect of the invention is the administration of a combinationof an ACE inhibitor and a compound of formula I.

Examples of ACE inhibitors are those disclosed in the article by Wyvrattet al., cited above, and in the following U.S. patents: U.S. Pat. Nos.4,105,776, 4,468,519, 4,555,506, 4,374,829, 4,462,943, 4,470,973,4,470,972, 4,350,704, 4,256,761, 4,344,949, 4,508,729, 4,512,924,4,410,520 and 4,374,847, all incorporated herein by reference; and thefollowing foreign patents or published patent applications:

British Specification No. 2095682 published Oct. 6, 1982 disclosesN-substituted-N-carboxyalkyl aminocarbonyl alkyl glycine derivativeswhich are said to be angiotensin converting enzyme inhibitors and havethe formula ##STR6## either (A) R^(b) and R₉ ^(b) are OH, 1-6C alkoxy,2-6C alkenyloxy, di-(1-6C alkyl)amino-(1-6C) alkoxy, 1-6C hydroxyalkoxy,acylamino-(1-6C)alkoxy, acyloxy-(1-6C)alkoxy, aryloxy,aryloxy-(1-6C)alkoxy, NH₂, mono- or di-(1-6C alkyl)amino, hydroxyaminoor aryl-(1-6C)alkylamino;

R₁ ^(b) -R₅ ^(b), R₇ ^(b) and R₈ ^(b) are 1-20C alkyl, 2-20C alkenyl,2-20C alkynyl, aryl, aryl-(1-6C) alkyl having 7-12C orheterocyclyl-(1-6C)alkyl having 7-12C;

R₆ ^(b) is cycloalkyl, polycycloalkyl, partly saturated cycloalkyl orpolycycloalkyl, cycloalkyl-(1-6C)alkyl having 3-20C, 6-10C aryl,aryl-(1-6C)alkyl, aryl-(2-6C)alkenyl or aryl-(2-6C) alkynyl; or

R₂ ^(b) and R₃ ^(b) together with the C and N atoms to which they areattached or R₃ ^(b) and R₅ ^(b) together with the N and C atoms to whichthey are attached form an N-heterocycle containing 3-5C or 2-4C and a Satom;

all alkyl, alkenyl and alkynyl are optionally substituted by OH, 1-6Calkoxy, thio(sic), 1-6C alkylthio, NH₂, mono-or di(1-6C alkyl)amino,halogen or NO₂ ;

all `cycloalkyl` groups (including poly and partially unsaturated) areoptionally substituted by halogen, 1-6C hydroxyalkyl, 1-6C alkoxy,amino-(1-6C alkyl)amino, di(1-6C alkyl)amino, SH, 1-6C alkylthio, NO₂ orCF₃ ; and aryl groups are optionally substituted by OH, 1-6C alkoxy,NH₂, mono- or di-(1-6C alkyl) amino, SH, 1-6C alkylthio, 1-6Chydroxyalkyl, 1-6C aminoalkyl, 1-6C thioalkyl, NO₂, halogen, CF₃, OCH₂O, ureido or guanidino; or (B) R^(b) and R₉ ^(b) are H or 1-6C alkoxy;

R₁ ^(b) and R₂ ^(b) are H, 1-6C alkyl, aryl-(1-6C) alkyl having 7-12C orheterocyclyl-(1-6C) alkyl having 6-12C;

R₃ ^(b) -R₅ ^(b), R₇ ^(b) and R₈ ^(b) are H or 1-6C alkyl;

R₆ ^(b) is cycloalkyl, polycycloalkyl, partly saturated cycloalkyl orpolycycloalkyl, cycloalkyl-(1-6C) alkyl having 3-20C, aryl oraryl-(1-6C) alkyl; and

aryl has 6-10C and is optionally substituted by 1-6C alkyl, 2-6Calkenyl, 2-6C alkynyl, OH, 1-6C alkoxy, NH₂, mono-or di-(1-6C alkyl)amino, SH, 1-6C alkylthio, 1-6C hydroxyalkyl, 1-6C aminoalkyl, 1-6Cthioalkyl, NO₂, halogen, CF₃, OCH₂ O, ureido or guanidino;

European Patent Application 0 050 800 published May 5, 1982 disclosescarboxyalkyl dipeptides derivatives which are said to be angiotensinconverting enzyme inhibitors and have the formula ##STR7## or apharmaceutically acceptable salt thereof, wherein R^(c) and R^(6c) arethe same or different and are hydroxy, lower alkoxy, lower alkenyloxy,dilower alkylamino lower alkoxy, acylamino lower alkoxy, acyloxy loweralkoxy, aryloxy, aryllower alkoxy, amino, lower alkylamino, diloweralkylamino, hydroxyamino, aryllower alkylamino, or substituted aryloxyor substituted aryllower alkoxy wherein the substituent is methyl, haloor methoxy; R^(1c) is hydrogen, alkyl of from 1 to 10 carbon atoms,substituted lower alkyl wherein the substituent is hydroxy, loweralkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substitutedheteroaryloxy, amino, lower alkylamino, diloweralkylamino, acylamino,arylamino, substituted arylamino, guanidino, imidazolyl, indolyl, loweralkylthio, arylthio, substituted arylthio, carboxy, carbamoyl, loweralkoxy carbonyl, aryl, substituted aryl, aralkyloxy, substitutedaralkyloxy, aralkylthio or substituted aralkylthio, wherein the aryl orheteroaryl portion of said substituted aryloxy, heteroaryloxy,arylamino, arylthio, aryl, aralkyloxy, aralkylthio group is substitutedwith a group selected from halo, lower alkyl, hydroxy, lower alkoxy,amino, aminomethyl, carboxyl, cyano, or sulfamoyl; R^(2c) and R^(7c) arethe same or different and are hydrogen or lower alkyl; R^(3c) ishydrogen, lower alkyl, phenyl lower alkyl, aminoethylphenyl lower alkyl,hydroxyphenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl,amino lower alkyl, dimethylamino lower alkyl, guanidino lower alkyl,imidazolyl lower alkyl, indolyl lower alkyl, or lower alkyl thio loweralkyl; R^(4c) and R^(5c) are the same or different and are hydrogen,lower alkyl or Z.sup. c, or R^(4c) and R^(5c) taken together form agroup represented by Q^(c), U^(c), V^(c), Y^(c), D^(c) or E^(c),wherein;

Z^(c) is ##STR8## wherein X^(1c) and X^(2c) independent of each otherare O, S or CH₂, R^(8c) and R^(9c) independent of each other are loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl having 3 to 8 carbonatoms, hydroxy lower alkyl, or --(CH₂)_(n) ^(c) Ar^(c), wherein n^(c) is0, 1, 2 or 3 and Ar^(c) is unsubstituted or substituted phenyl, furyl,thienyl or pyridyl, wherein said substituted phenyl, furyl, thienyl orpyridyl groups are substituted with at least one group that isindependently selected from C₁ to C₄ alkyl, lower alkoxy, loweralkylthio, halo, CF₃ and hydroxy, or R^(8c) and R^(9c) taken togetherform a bridge W^(c), wherein W^(c) is a single bond or a methylenebridge or a substituted methylene bridge when at least one of X^(1c) andX^(2c) is methylene, or W^(c) is an alkylene or substituted alkylenebridge having 2 or 3 carbon atoms, said substituted methylene bridge orsaid substituted alkylene bridge having one or two substituents selectedfrom lower alkyl, aryl and aryl lower alkyl groups, and p^(c) is 0, 1 or2; with the proviso that at least one of R^(4c) and R^(5c) is Z^(c),with the proviso that if R^(4c) is Z^(c) and p^(c) is 0 then X^(1c) andX^(2c) must both be methylene, and with the proviso that if X^(1c) andX^(2c) are both methylene then R^(8c) and R^(9c) must form an alkylenebridge W^(c) ;

Q^(c) is ##STR9## wherein R^(8c), R^(9c), X^(1c) and X^(2c) are asdefined above, p^(c) is 0, 1 or 2, q^(c) is 0, 1 or 2, with the provisothat the sum of p^(c) and q^(c) must be 1, 2 or 3, with the proviso thatif p^(c) is 0 then X^(1c) and X^(2c) must be methylene, and with theproviso that if X^(1c) and X^(2c) are methylene then R^(8c) and R^(9c)taken together form a bridge W^(c), wherein W^(c) is as defined above;

V^(c) is ##STR10## wherein R^(8c), R^(9c), X^(1c) and X^(2c) are asdefined above, p^(c) is 0, 1 or 2 and q^(c) is 0, 1 or 2, with theproviso that the sum of p^(c) and q^(c) is 1, 2 or 3, with the provisothat if X^(1c) and X^(2c) are CH₂ then R^(8c) and R^(9c) taken togetherform a bridge W^(c), wherein W^(c) is as defined above;

U^(c) is ##STR11## wherein W^(c) is as defined above (except that W^(c)may also be a methylene bridge when X^(1c) and X^(2c) are oxygen orsulfur), X^(1c) and X^(2c) are as defined above, p^(c) is 0, 1 or 2,q^(c) is 0, 1 or 2, with the proviso that the sum of p^(c) and q^(c) is1 or 2, and with the proviso that if p^(c) is 0, X^(1c) must be CH₂ ;

Y^(c) is ##STR12## wherein G^(c) is oxygen, sulfur or CH₂, a^(c) is 2, 3or 4 and b^(c) is 1, 2, 3, 4 or 5, with the proviso that the sum ofa^(c) and b^(c) is 5, 6 or 7 or G^(c) is CH₂, a^(c) is 0, 1, 2 or 3,b^(c) is 0, 1, 2 or 3 with the proviso that the sum of a^(c) and b^(c)is 1, 2 or 3, with the proviso that the sum of a^(c) and b^(c) may be 1,2 or 3 only if R^(1c) is lower alkyl substituted with aralkylthio oraralkyloxy;

D^(c) is ##STR13## wherein F^(c) is O or S, j^(c) is 0, 1 or 2 and k^(c)is 0, 1 or 2, with the proviso that the sum of j^(c) and k^(c) must be1, 2 or 3, and m^(c) is 1, 2 or 3 and t^(c) is 1, 2 or 3, with theproviso that the sum of m^(c) and t^(c) must be 2, 3 or 4;

E^(c) is ##STR14## wherein L^(c) is O or S, u^(c) is 0, 1 or 2 and v^(c)is 0, 1 or 2, with the proviso that the sum of u^(c) and v^(c) must be 1or 2, and h^(c) is 1 or 2 and s^(c) is 1 or 2, with the proviso that thesum of h^(c) and s^(c) must be 2 or 3;

European Patent Application 0 079 522 published May 25, 1983 disclosesN-carboxymethyl(amidino) lysyl-proline compounds which are said to beangiotensin converting enzyme inhibitors and have the formula where##STR15## wherein: R^(d) and R^(2d) are independently hydrogen;loweralkyl; aralkyl; or aryl;

R^(1d) is hydrogen; branched or straight chain C₁₋₁₂ alkyl and alkenyl;C₃ -C₉ cycloalkyl and benzofused alkyl; substituted loweralkyl where thesubstituents are halo, hydroxy loweralkoxy, aryloxy, amino, mono- ordiloweralkylamino, acylamino, arylamino, guanidino, mercapto,loweralkylthio, arylthio, carboxy, carboxamido, or loweralkoxycarbonyl;aryl; substituted aryl where the substituents are loweralkyl,loweralkoxy, or halo; arloweralkyl; arloweralkenyl; heteroarloweralkyl;heteroarloweralkenyl; substituted arloweralkyl, substitutedarloweralkenyl, substituted heteroarloweralkyl, or substitutedheteroarloweralkenyl where the aryl and heteroaryl substituents arehalo, dihalo, loweralkyl, hydroxy, loweralkoxy, amino, aminoloweralkyl,acylamino, mono- or diloweralkylamino, carboxyl, haloloweralkyl, nitro,cyano, or sulfonamido, and where the loweralkyl portion of arloweralkylmay be substituted by amino, acylamino, or hydroxyl; ##STR16## where:X^(d) and Y^(d) taken together are --CH₂ --CH₂ --; --CH(R^(5d))--S--;--C(O)--CH₂ --; --CH₂ --C(O)--; --C(O)--O--; --C(O)--S--; --CH₂--CH(OR^(4d))--; --C(O)--N(R^(4d))--; or --CH₂ --C(R^(4d))--R^(5d) ;

R^(4d) is hydrogen; loweralkyl; aryl; substituted aryl;

R^(5d) is hydrogen; loweralkyl; aryl or substituted aryl;

n^(d) is 1 to 3;

W^(d) is absent; --CH₂ --; or --C(O)--;

Z^(d) is --(CH₂)_(m) ^(d), where m^(d) is 0 to 2, provided that m^(d)may not be 0 and W^(d) may not be absent at the same time; and

R^(6d) is hydrogen; loweralkyl; halo; or OR^(4d) ;

R^(2d) is --(CH₂)_(r) ^(d) --B^(d) --(CH₂)_(s) ^(d) --NR^(7d) R^(15d)

where

r^(d) and s^(d) are independently 0 to 3;

B^(d) is absent; --O--; --S--; or --NR^(8d;)

where R^(8d) is hydrogen; loweralkyl; alkanoyl; or aroyl; and

R^(7d) is ##STR17## where R^(9d) is loweralkyl; aralkyl; aryl;heteroaryl; or heteroarloweralkyl and these groups substituted byhydroxy, lower alkoxy or halo; carboxyl; carboxamido; nitromethenyl.

R^(10d) is hydrogen; loweralkyl; aryl; or amidino; R^(11d) is hydrogen;loweralkyl; cyano; amidino; aryl; aroyl; loweralkanoyl;--C(O)--NHR^(13d) ; --C(O)--OR^(13d) ; --NO₂ ; --SO₂ NH₂ ; or SO₂R^(13d;)

R^(12d) is hydrogen; loweralkyl; halo; aralkyl; amino; cyano; mono- ordiloweralkylamino; or OR^(4d) ;

R13d is hydrogen; loweralkyl; or aryl;

R15d is hydrogen; lower alkyl; aralkyl; or aryl; ##STR18## constitute abasic heterocycle of 5 or 6 atoms or benzofused analogs thereof andoptionally containing 1-3 N atoms, an oxygen, a sulfur, an S═O, or anSO₂ group optionally substituted by amino, lower alkyl amino,diloweralkyl amino, lower alkoxy, or aralkyl groups;

R^(3d) is C₃₋₈ cycloalkyl and benzofused C₃₋₈ cycloalkyl;perhydrobenzofused C₃₋₈ cycloalkyl; aryl; substituted aryl; heteraryl;substituted heteroaryl;

R^(14d) is hydrogen or loweralkyl; and, a pharmaceutically acceptablesalt thereof;

European Patent 79022 published May 18, 1983 discloses N-aminoacyl-azabicyclooctane carboxylic acid derivatives which have the formula##STR19## hydrogen atoms at ring positions 1 and 5 are cis to each otherand the 3-carboxy group has the endo orientation;

R₁ ^(e) is H, allyl, vinyl or the side chain of an optionally protectednaturally occurring α-amino acid;

R₂ ^(e) is H, 1-6C alkyl, 2-6C alkenyl or aryl(1-C alkyl);

Y^(e) is H or OH and Z^(e) is H, or Y^(e) and Z^(e) together oxygen;

X^(e) is 1-6C alkyl, 2-6C alkenyl, 5-9C cycloalkyl, 6-12C aryl(optionally substituted by one to three 1-4C alkyl or alkoxy, OH, halo,nitro, amino (optionally substituted by one or two 1-4C alkyl), ormethylenedioxy) or indol-3-yl);

European Patent 46953 published Mar. 10, 1982 discloses N-aminoacyl-indoline and tetrahydro isoquinoline carboxylic acids which areangiotensin coverting enzyme inhibitors and have the formula ##STR20##R₁ ^(f) and R₂ ^(f) are each 1-6C alkyl, 2-6C alkenyl, 5-7C cycloalkyl,5-7C cycloalkenyl, 7-12C cycloalkylalkyl, optionally partiallyhydrogenated 6-10C aryl, 7-14C aralkyl or 5-7 membered monocyclic or8-10 membered bicyclic heterocyclyl containing 1 or 2 S or O and/or 1-Natoms; all R₁ ^(f) and R₂ ^(f) groups are optionally substituted, R₃^(f) is H, 1-6C alkyl, 2-6C alkenyl or 7-14C aralkyl.

The following Table II lists ACE inhibitors preferred for use in thecombination of this invention.

                                      TABLE II                                    __________________________________________________________________________    PREFERRED ACE INBIBITORS                                                      __________________________________________________________________________     ##STR21##                                                                          R        R.sub.1                                                                         R.sub.2  R.sub.3                                             __________________________________________________________________________    spirapril                                                                           C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                      Et                                                                              CH.sub.3                                                                                ##STR22##                                          enalapril                                                                           C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                      Et                                                                              CH.sub.3 prolyl                                              ramipril                                                                            C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                      Et                                                                              CH.sub.3                                                                                ##STR23##                                          perindopril                                                                         CH.sub.3 CH.sub.2 CH.sub.2                                                             Et                                                                              CH.sub.3                                                                                ##STR24##                                          indolapril                                                                          C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                      Et                                                                              CH.sub.3                                                                                ##STR25##                                          lysinopril                                                                          C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                      H NH.sub.2 (CH.sub.2).sub.4                                                              prolyl                                              quinapril                                                                           C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                      Et                                                                              CH.sub.3                                                                                ##STR26##                                          pentopril (NHCH.sub.2)                                                              CH.sub.3 Et                                                                              CH.sub.3                                                                                ##STR27##                                          cilazapril                                                                          C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                      H                                                                                ##STR28##                                                                              ##STR29##                                          __________________________________________________________________________                 ##STR30##                                                                    R       R.sub.2                                                   __________________________________________________________________________    captopril   H       prolyl                                                    zofenopril  C.sub.6 H.sub.5 CO                                                                     ##STR31##                                                pivalopril                                                                                 ##STR32##                                                                             ##STR33##                                                __________________________________________________________________________             ##STR34##                                                                    R        R.sup.1        R.sup.2                                       __________________________________________________________________________    fosinopril                                                                            C.sub.6 H.sub.5 (CH.sub.2).sub.4                                                        ##STR35##     C.sub.6 H.sub.5                               __________________________________________________________________________

Compounds of the present invention can be made by methods well known tothose skilled in the art. An example of a synthetic method is shownbelow. Acid II is converted into isocyanate III, for example by reactionwith diphenylphosphorylazide at elevated temperatures (e.g. 80° C.) inthe presence of a base such as triethylamine in a solvent such astoluene. The isocyanate need not be isolated. The isocyanate III istreated with benzyl alcohol to produce the benzyl carbamate, IV. Thecarbamate IV is then converted to an amine salt, V, for example bytreatment with HBr in acetic acid. The salt V is then reacted with acompound of formula VI in an inert solvent such as methylene chloride inthe presence of a base such as triethylamine at room temperature toobtain compounds of formula I: ##STR36## wherein Q, R₁, R₂ and m are asdefined above, and wherein Z is an acid activating group such as chloro,azido or alkoxycarbonyloxy. Alternatively, Z is hydroxy, in which caseactivation can be accomplished by a peptide coupling agent such as acarbodiimide.

It is apparent that using methods well known to those skilled in theart, compounds of formula I can be converted to different compounds offormula I by appropriate reaction of the Q and/or R₃ variables, e.g. athioester can be converted to a mercaptan, and an acid can be convertedto an amide or an ester to an acid.

Compounds of formula II and VI are known in the art or can be preparedby methods well known in the art.

We have found that the novel compounds of the present invention areeffective in treating cardiovascular disorders such as congestive heartfailure, edema, renal insufficiency and various types of hypertension,particularly volume expanded hypertension. These novel compounds enhanceboth the magnitude and duration of the antihypertensive and natriureticeffects of endogenous ANF. Administration of a combination of anN-(mercaptoalkyl)amide and an ACE inhibitor provides an antihypertensiveand anti-congestive heart failure effect greater than either theN-(mercaptoalkyl)amide or ACE inhibitor alone. Administration of acombination of an N-(mercaptoalkyl)amide of formula I and an exogenousANF or ACE inhibitor is therefore particularly useful in treatinghypertension or congestive heart failure.

In addition to the compound aspect, the present invention therefore alsorelates to treating cardiovascular disorders with anN-(mercaptoalkyl)amide of formula I or with an N-(mercaptoalkyl)amide offormula I in combination with an ANF or an ACE inhibitor, which methodscomprise administering to a mammal in need of such treatment an amountof the N-(mercaptoalkyl)amide effective to treat hypertension orcongestive heart failure or an amount of a combination of anN-(mercaptoalkyl)amide and ANF or ACE inhibitor effective to treathypertension or congestive heart failure. The drug or combination ofdrugs is preferably administered in a pharmaceutically acceptablecarrier, e.g. for oral or parenteral administration. The combinations ofdrugs may be co-administered in a single composition, or components ofthe combination therapy may be administered separately. Where thecomponents are administered separately, any convenient combination ofdosage forms may be used, e.g. oral N-(mercaptoalkyl)amide/oral ANF,oral N-(mercaptoalkyl)amide/parenteral ACE inhibitor, parenteralN-(mercaptoalkyl)amide/oral ANF, parenteralN-(mercaptoalkyl)amide/parenteral ACE inhibitor.

When the components of a combination of an N-(mercaptoalkyl)amide and anANF are administered separately, it is preferred that theN-(mercaptoalkyl)amide be administered first.

The present invention also relates to a pharmaceutical compositioncomprising an N-(mercaptoalkyl)amide for use in treating hypertension orcongestive heart failure, to a pharmaceutical composition comprisingboth an N-(mercaptoalkyl)amide and an ANF, and to a pharmaceuticalcomposition comprising both an N-(mercaptoalkyl)amide and an ACEinhibitor.

The antihypertensive effect of N-(mercaptoalkyl)amides was determinedaccording to the following procedure:

Male Sprague Dawley rats weighing 100-150 g were anesthetized with etherand the right kidney was removed. Three pellets containing DOC acetate(desoxycorticosterone acetate, DOCA, 25 mg/pellet) were implantedsubcutaneously. Animals recovered from surgery, were maintained onnormal rat chow and were allowed free access to a fluid of 1% NaCl and0.2% KCl instead of tap water for a period of 17-30 days. This procedureresults in a sustained elevation in blood pressure and is a slightmodification of published procedures (e.g. Brock et al., 1982) that havebeen used to produce DOCA salt hypertension in the rat.

On the day of study, animals were again anesthetized with ether and thecaudal artery was cannulated for blood pressure measurement. Patency ofthe caudal artery cannula was maintained with a continuous infusion ofdextrose in water at a rate of 0.2 ml/hr. Animals were placed intorestraining cages where they recovered consciousness. Blood pressure wasmeasured from caudal artery catheter using a Statham pressure transducerattached to a Beckman oscillographic recorder. In addition, acardiovascular monitoring device (Buxco Electronics, Inc.) and a digitalcomputer were used to calculate average blood pressures.

After an equilibration period of at least 1.5 hr., animals were dosedsubcutaneously (1 ml/kg) with vehicle (methylcellulose, hereinafter MC)or N-(mercaptoalkyl)amide and blood pressure was monitored for the next4 hours.

A similar procedure can be used to determine the effect ofN-(mercaptoalkyl)amides in combination with ACE inhibitors.

The antihypertensive effect of N-(mercaptoalkyl)amides in combinationwith ANF can be determined according to the following procedures:

Male spontaneously hypertensive rats (SHR), 16-18 weeks old, 270-350 g,are anesthetized with ether and the abdominal aorta is cannulatedthrough the tail artery. The animals are then placed into restrainers torecover from anesthesia (in less than 10 min.) and remain insidethroughout the experiments. Through a pressure transducer (Gould P23series) analog blood pressure signals are registered on a Beckman 612recorder. A Buxco digital computer is used to obtain mean arterialpressures. Patency of the arterial cannula is maintained with acontinuous infusion of 5% dextrose at 0.2 ml/hr. Animals are allowed a90-min equilibration period. The animals first undergo a challenge withan ANF such as atriopeptin II (AP II) or AP28 30 μg/kg iv and at the endof 60 min. are treated with drug vehicle or an N-(mercaptoalkyl)amidesubcutaneously. A second ANF challenge is administered 15 min. later andblood pressure is monitored for the next 90 min.

The antihypertensive effect in SHR of N-(mercaptoalkyl)amides and ACEinhibitors, alone and in combination, can be determined as follows:

Animals are prepared for blood pressure measurement as described above.After stabilization, animals are dosed subcutaneously or orally withtest drugs or placebo and blood pressure is monitored for the next 4 hr.

Using the above test procedures, a 1 mg/kg dose (po) of3-[N[1(R)-mercapto-3-(2-methylphenyl)-2-propyl]aminocarbonyl]benzoicacid has been found to produce a 47 mmHg drop in blood pressure in theDOCA salt model and a 19 mm Hg drop in blood pressure (30 mg/kg sc) inthe ANF potentiation procedure.

The compounds having structural formula I have also been found toinhibit the activity of enzymes designated enkephalinases. The compoundsare particularly useful for the inhibition of enkephalinase A, which isderived from the striata of both rats and humans. In in vitro tests,using test procedures for enkephalinase A inhibition well known to thoseskilled in the art, selected compounds having structural formula I havebeen found to inhibit the activity of the aforementioned enzyme.Therefore, the present invention also relates to a method of inhibitingthe action of enkephalinases in a mammal thereby to elicit an analgesiceffect with a compound of formula I and to analgesic pharmaceuticalcompositions comprising compounds of formula I.

The use of atrial natriuretic peptides in the treatment ofnephrotoxicity associated with the immunosuppressive cyclosporin wasreported by Capasso et al in the American Journal of Hypertension, 3, 3(1990), p. 204-210. Since compounds of this invention enhance endogenousANF, they can be used alone to treat nephrotoxicity, or they can beadministered in combination with exogenous ANF.

The compositions of this invention comprise an N-(mercaptoalkyl)amide,an N-(mercaptoalkyl)amide and an ANF or an N-(mercaptoalkyl)amide and anACE inhibitor in combination with a pharmaceutically acceptable carrierfor administration to mammals. A variety of pharmaceutical forms issuitable, preferably for oral or parenteral administration, althoughmechanical delivery systems such as transdermal dosage forms are alsocontemplated.

The daily dose of the compound or combinations of this invention fortreatment of hypertension or congestive heart failure is as follows: forN-(mercaptoalkyl)amides alone the typical dosage is 0.1 to 10 mg/kg ofmammalian weight per day administered in single or divided dosages; forthe combination of an N-(mercaptoalkyl)amide and an ANF, the typicaldosage is 0.1 to 10 mg of N-(mercaptoalkyl)amide/kg mammalian weight perday in single or divided dosages plus 0.001 to 0.1 mg ANF/kg ofmammalian weight per day, in single or divided dosages, and for thecombination of an N-(mercaptoalkyl)amide and an ACE inhibitor, thetypical dosage is 0.1 to 10 mg of N-(mercaptoalkyl)amide/kg mammalianweight per day in single or divided dosages plus 0.1 to 30 mg ACEinhibitor/kg of mammalian weight per day in single or divided dosages.The exact dose of any component or combination to be administered isdetermined by the attending clinician and is dependent on the potency ofthe compound administered, the age, weight, condition and response ofthe patient.

Generally, in treating humans having hypertension or congestive heartfailure, the compounds or combinations of this invention may beadministered to patients in a dosage range as follows: for treatmentwith an N-(mercaptoalkyl)amide alone, about 5 to about 500 mg per dosegiven 1 to 4 times a day, giving a total daily dose of about 5 to 2000mg per day; for the combination of an N-(mercaptoalkyl)amide and ANF,about 5 to about 500 mg N-(mercaptoalkyl)amide per dose given 1 to 4times a day and about 0.01 to about 1 mg ANF given 1 to 6 times a day(total daily dosage range of 5 to 2000 mg day and 0.01 to 6 mg/day,respectively); and for the combination of an N-(mercaptoalkyl)amide andan ACE inhibitor, about 5 to about 500 mg N-(mercaptoalkyl)amide perdose given 1 to 4 times a day and about 5 to about 50 mg ACE inhibitorgiven 1 to 3 times a day (total daily dosage range of 5 to 2000 mg/dayand 5 to 150 mg/day, respectively). Where the components of acombination are administered separately, the number of doses of eachcomponent given per day may not necessarily be the same, e.g. where onecomponent may have a greater duration of activity, and will thereforeneed to be administered less frequently.

To produce an analgesic effect, compounds of this invention will beadministered in a dosage range of from about 1 to about 100 mg/kg. Thedoses are to be administered at intervals of from 3 to 8 hours. However,the quantity and frequency of dosage will depend upon such factors asthe severity of the pain, the general physical condition of the patient,the age and weight of the patient, and other factors recognized by theskilled clinician.

For treatment of edema, renal insufficiency or nephrotoxicity associatedwith immunosuppressive therapy, dosage ranges of the compounds of thisinvention are the same as for treatment of hypertension with the use ofN-(mercaptoalkyl)amides alone or in combination with ANF.

Typical oral formulations include tablets, capsules, syrups, elixirs andsuspensions. Typical injectable formulations include solutions andsuspensions.

The typical acceptable pharmaceutical carriers for use in theformulations described above are exemplified by: sugars such as lactose,sucrose, mannitol and sorbitol, starches such as cornstarch, tapiocastarch and potato starch; cellulose and derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and methyl cellulose; calciumphosphates such as dicalcium phosphate and tricalcium phosphate; sodiumsulfate; calcium sulfate; polyvinylpyrrolidone, polyvinyl alcohol;stearic acid; alkaline earth metal stearates such as magnesium stearateand calcium stearate, stearic acid, vegetable oils such as peanut oil,cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationicand anionic surfactants; ethylene gylcol polymers; beta-cyclodextrin;fatty alcohols and hydrolyzed cereal solids; as well as other nontoxiccompatible fillers, binders, disintegrants, buffers, preservatives,antioxidants, lubricants, flavoring agents, and the like commonly usedin pharmaceutical formulations.

Since the present invention relates to treatment of hypertension orcongestive heart failure with a combination of active ingredientswherein said active ingredients may be administered separately, theinvention also relates to combining separate pharmaceutical compositionsin kit form. That is, two kits are contemplated, each combining twoseparate units: an N-(mercaptoalkyl)amide pharmaceutical composition andan ANF pharmaceutical composition in one kit and anN-(mercaptoalkyl)amide pharmaceutical composition and an ACE inhibitorpharmaceutical composition in a second kit. The kit form is particularlyadvantageous when the separate components must be administered indifferent dosage forms (e.g. oral and parenteral) or are administered atdifferent dosage intervals.

Following are examples of procedures for preparing compounds of formulaI.

PREPARATION 1 1(R)-Acetylthio-3-(2-Methylphenyl)-2-PropylamineHydrobromide

Heat for 1 hr at 80° C. a solution of2(S)-acetylthiomethyl-3-(2-methylphenyl)propionic acid (6.0 g=24 mmol),diphenylphosphoryl azide (6.6 g=24 mmol) and triethylamine (2.4 g=24mmol) in toluene (90 ml). Allow to cool, add benzyl alcohol (3.1 g=29mmol) and heat at 80° C. for 1 hr. Concentrate in vacuo and partitionwith EtOAc and 1.0N NaHCO₃. Dry and concentrate to obtain crude benzylN-[1(R)-acetylthio-3-(2-methylphenyl)-2-propyl]carbamate. Purify bysilica gel chromatography with 2:1 hexane/Et₂ O to obtain a white solid,m.p. 73°-80° C., [α]_(D) ²⁶ =-2.0° (EtOH).

Add the above carbamate (3.2 g=9.0 mmol) to 33% HBr/HOAc (20 ml). After4.5 hr, concentrate in vacuo. Treat the solid with Et₂ O (200 ml),filter and dry to obtain the title compound as a pale orange solid, m.p.137°-8° C.

EXAMPLE 1 Methyl4-[N-[1(R)-Acetylthio-3-(2-Methylphenyl)-2-Propyl]Aminocarbonyl]Benzoate

To the hydrobromide of Preparation 1 (0.45 g=1.5 mmol) and4-(methoxycarbonyl)benzoyl chloride (0.29 g=1.5 mmol) in CH₂ Cl₂ (25ml), add Et₃ N (0.30 g=3.0 mmol) in CH₂ Cl₂ (10 ml). After 1 hr,concentrate and partition between EtOAc and 1.0N HCl. Dry over MgSO₄ andconcentrate. Chromatograph the solid on silica, eluting with 1:1 Et₂O/hexane to obtain the title compound as a white solid, m.p. 136°-40°C., [α]_(D) ²⁶ =-19.3° (EtOH).

EXAMPLE 24-[N-[1(R)-Mercapto-3-(2-Methylphenyl)-2-Propyl]Aminocarbonyl]BenzoicAcid

To the ester of Example 1 (0.14 g=0.36 mmol) in MeOH (8 ml,nitrogen-purged) add 1.00N NaOH (2.0 ml, nitrogen-purged). Stir 0.5 hr,concentrate in vacuo and add 1.0N HCl (2.0 ml). Collect the solid, washwith water and dry to obtain the title compound as a white solid, m.p.195°-7° C., [α]_(D) ²⁶ =+64.9° (EtOH).

EXAMPLE 3 Methyl3-[N-[1(R)-Acetylthio-3-(2-Methylphenyl)-2-Propyl]Aminocarbonyl]Benzoate

In a fashion similar to Example 1, employ 3-(methoxycarbonyl)benzoylchloride to prepare the title compound, a white solid, m.p. 118° C.,[α]_(D) ²⁶ =-22.5° (EtOH).

EXAMPLE 43-[N-[1(R)-Mercapto-3-(2-Methylphenyl)-2-Propyl]Aminocarbonyl]BenzoicAcid

In a manner similar to Example 2, convert the ester of Example 3 to thetitle compound, a white solid, m.p. 157°-60° C., [α]_(D) ²⁶ =+57.2°(EtOH).

EXAMPLE 5 Methyl2-[N-[1(R)-Acetylthio-3-(2-Methylphenyl)-2-Propyl]Aminocarbonyl]Benzoate

In a manner similar to Example 1, employ 2-(methoxycarbonyl)benzoylchloride to prepare the title compound (eluted with Et₂ O), a whitesolid, [α]_(D) ²⁶ =-12.2° (EtOH).

EXAMPLE 62-[N-[1(R)-Mercapto-3-(2-Methylphenyl)-2-Propyl]Aminocarbonyl]BenzoicAcid

In a manner similar to Example 2, convert the ester of Example 5 to thetitle compound, a white solid, [α]_(D) ²⁶ =+36.3° (EtOH), FAB-MS:M+1=330.

EXAMPLE 7 Methyl3-[N-[1(R)-Acetylthio-3-(2-Methylphenyl)-2-Propyl]Aminocarbonyl]-5-Nitrobenzoate

Heat 3-methoxycarbonyl-5-nitrobenzoic acid (2.0 g=8.9 mmol) with SOCl₂(2.1 g=18 mmol) in toluene at reflux 1 hr. Concentrate to obtain3-methoxycarbonyl-5-nitrobenzoyl chloride, m.p. 66°-8° C.

In a manner similar to Example 1, employ this acid chloride to preparethe title compound, a gum, [α]_(D) ²⁶ =-13.6° (EtOH).

EXAMPLE 83-[N-[1(R)-Mercapto-3-(2-Methylphenyl)-2-Propyl]Aminocarbonyl]-5-NitrobenzoicAcid

In a manner similar to Example 2, convert the ester of Example 7 to thetitle compound, a yellow solid, [α]_(D) ²⁶ =+61.5° (EtOH).

EXAMPLE 94-[N-[1(R)-Acetylthio-3-(2-Methylphenyl)-2-Propyl]Aminocarbonyl]PhthalicAcid

To the hydrobromide of Preparation 1 (0.45 g=1.5 mmol) and4-(chlorocarbonyl)phthalic anhydride (0.31 g=1.5 mmol) in CH₂ Cl₂ (25ml), add Et₃ N (0.30 g=3.0 mmol) in CH₂ Cl₂ (10 ml). After 2 hr,concentrate and partition between EtOAc and 1.0N HCl. Dry over MgSO₄ andconcentrate to obtain a white solid, m.p. 163°-5° C.

Treat this solid with 1:1 THF-H₂ O (20 ml) for 18 hr. Concentrate toobtain the title compound, a white solid, [α]_(D) ²⁶ =-14.5° (EtOH).

EXAMPLE 104-[N-[1(R)-Mercapto-3-(2-Methylphenyl)-2-Propyl]Aminocarbonyl]PhthalicAcid

In a manner similar to Example 2, convert the acetyl compound of Example9 to the title compound, a white foam, [α]_(D) ²⁶ =+54.5° (EtOH).

EXAMPLE 11N-[1(R)-Acetylthio-3-(2-Methylphenyl)-2-Propyl]Pyridine-4-Carboxamide

To the hydrobromide of Preparation 1 (0.45 g=1.5 mmol), isonicotinoylchloride hydrochloride (0.32 g=1.8 mmol), and 4-dimethylaminopyridine(0.18 g=1.5 mmol) in CH₂ Cl₂ (15 ml), add Et₃ N (0.47 g=4.7 mmol) in CH₂Cl₂ (5 ml). Stir 0.5 hr, concentrate and partition between EtOAc and H₂O. Dry over MgSO₄ and concentrate. Chromatograph the oil on silica,eluting with 4% MeOH/CH₂ Cl₂ to obtain the title compound as a whitesolid, m.p. 132° C., [α]_(D) ²⁶ =-24.1° (EtOH).

EXAMPLE 12N-[1(R)-Mercapto-3-(2-Methylphenyl)-2-Propyl]Pyridine-4-Carboxamide

In a manner similar to Example 2, convert the acetyl compound of Example11 to the title compound, a white solid, [α]_(D) ²⁶ =+50.5° (EtOH).

The following formulations exemplify some of the dosage forms of thecompositions of this invention. In each, the term "active ingredient"designates a compound of formula I, preferably3-[N-[1(R)-mercapto-3-(2-methylphenyl)-2-propyl]aminocarbonyl]benzoicacid. However, this compound can be replaced by equally effectiveamounts of other compounds of formula I.

EXAMPLE A

    ______________________________________                                        Tablets                                                                       No.  Ingredient          mg/tablet mg/tablet                                  ______________________________________                                        1    Active Compound     100       500                                        2    Lactose USP         122       113                                        3    Corn Starch, Food Grade, as a                                                                      30        40                                             10% Paste in Purified Water                                              4    Corn Starch, Food Grade                                                                            45        40                                        5    Magnesium Stearate   3         7                                              Total               300       700                                        ______________________________________                                    

Method of Manufacture

Mix Items Nos. 1 and 2 in suitable mixer for 10-15 minutes. Granulatethe mixture with Item No. 3. Mill the damp granules through a coarsescreen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screenthe dried granules if necessary and mix with Item No. 4 and mix for10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress themixture to appropriate size and weight on a suitable tablet machine.

EXAMPLE B Capsules

    ______________________________________                                        No.   Ingredient       mg/capsule mg/capsule                                  ______________________________________                                        1     Active Compound  100        500                                         2     Lactose USP      106        123                                         3     Corn Starch, Food Grade                                                                         40         70                                         4     Magnesium Stearate NF                                                                           4          7                                                Total            250        700                                         ______________________________________                                    

Method of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. AddItem No. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

EXAMPLE C

    ______________________________________                                        Parenteral Preparation                                                        Ingredient           mg/vial  mg/vial                                         ______________________________________                                        Active Compound Sterile Powder                                                                     100      500                                             ______________________________________                                    

For reconstitution add sterile water for injection or bacteriostaticwater for injection.

We claim:
 1. A compound having the structural formula ##STR37## whereinR₁ is lower alkyl, cyclolower alkyl or aryl;R₂ is (COR₃)-aryl orsubstituted (COR₃)-aryl, wherein the substituents are 1-3 substituentsselected from the group consisting of carboxy, alkoxycarbonyl, loweralkyl, hydroxy, nitro, halo, lower alkoxy, cyclolower alkyl, cyano,trifluoromethyl, phenyl, phenoxy and phenylthio; R₃ is --OR₄ or --NR₄ R₅; R₄ and R₅ are independently selected from the group consisting ofhydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl andaryl lower alkyl, or R₄ and R₅ together with the nitrogen to which theyare attached form a 5-, 6- or 7-membered ring; Q is hydrogen or R₆ CO-;R₆ is hydrogen, lower alkyl or aryl; and m is 1 or 2;and thepharmaceutically acceptable salts thereof.
 2. A compound of claim 1wherein R₁ is phenyl or lower alkyl substituted phenyl and m is
 1. 3. Acompound of claim 1 wherein R₃ is hydroxy or lower alkoxy.
 4. A compoundof claim 1 wherein R₂ is (COR₃)-phenyl, nitro or carboxy-substituted(COR₃)-phenyl.
 5. A compound of claim 1 wherein Q is hydrogen or acyl.6. A compound of claim 1 which is:methyl4-[N-[1(R)-acetylthio-3-(2-methylphenyl)-2-propyl]aminocarbonyl]benzoate;4-[N-[1(R)-mercapto-3-(2-methylphenyl)-2-propyl]aminocarbonyl]benzoicacid; methyl3-[N-[1(R)-acetylthio-3-(2-methylphenyl)-2-propyl]aminocarbonyl]benzoate;3-[N-[1(R)-mercapto-3-(2-methylphenyl)-2-propyl]aminocarbonyl]benzoicacid; methyl3-[N-[1(R)-acetylthio-3-(2-methylphenyl)-2-propyl]aminocarbonyl]-5-nitrobenzoate;3-[N-[1(R)-mercapto-3-(2-methylphenyl)-2-propyl]aminocarbonyl]-5-nitrobenzoicacid;4-[N-[1(R)-acetylthio-3-(2-methylphenyl)-2-propyl]aminocarbonyl]phthalicacid;4-[N-[1(R)-mercapto-3-(2-methylphenyl)-2-propyl]aminocarbonyl]phthalicacid.
 7. A method for treating hypertension or congestive heart failurein mammals comprising administering to a mammal in need of suchtreatment an effective amount of a compound of claim
 1. 8. Apharmaceutical composition comprising an effective amount of a compoundof claim 1 in a pharmaceutically acceptable carrier.